Flavoring process using oxycyclic pyrazines

ABSTRACT

PROCESSES FOR ALTERING THE FLAVORS OF PRODUCTS, INCLUDING FOODSTUFFS AND TOBACCOS, WHICH COMPRISE ADDING THERETO A SMALL BUT EFFECTIVE AMOUNT OF AT LEAST ONE OXYCYCLIC PYRAZINE HAVING THE FORMULA   2,3-(-CH2-Y-CH2-),5-R1,6-R2,R3,R4,Z-PYRAZINE   WHEREIN Y IS-CH2-OR-CH2-CH2-; Z IS A CARBONYL OXYGEN, A HYDROXYL GROUP, OR AN ACYLOXY GROUP; AND R1, R2, R3, AND R4 ARE THE SAME OR DIFFERENT ND REPRESENT HYDROGEN, ALKYL, OR ALKYLENE; THE PRODUCTS SO PRODUCED; FLAVORING AND FLAVOR-ENHANCING COMPOSITIONS CONTAINING SUCH OXYCYCLIC PYRAZINES; AND NOVEL OXYCYCLIC PYRAZINES AND PROCESSES FOR THEIR PRODUCTION.

'United States 'Etent O1 flee U.S. Cl. 42665 Claims ABSTRACT OF THEDISCLOSURE Processes for altering the flavors of products, includingfoodstuffs and tobaccos, which comprise adding thereto a small buteffective amount of at least one oxycyclic pyrazine having the formulawherein Y is -CH or -CH -CH Z is a carbonyl oxygen, a hydroxyl group, oran acyloxy group; and R R R and R are the same or different andrepresent hydrogen, alkyl, or alkylene; the products so produced;flavoring and flavor-enhancing compositions containing such oxycyclicpyrazines; and novel oxycyclic pyrazines and processes for theirproduction.

This application is a division of our parent application Ser. No.29,639, filed Apr. 17, 1970, now United States Letters Patent 3,684,809.

BACKGROUND OF THE INVENTION The present invention relates to oxycyclicpyrazines and their use in processes and compositions for altering theflavors of various materials such as tobaccos, foodstufls, and the like,as well :as the novel pyrazines and processes for producing them.

Because of the tremendous consumption of foods, tobaccos, and othermaterials, there has been an increasing interest in substances andmethods for imparting flavors to such consumable materials. Thisinterest has been stimulated not only because of the inadequate quantityof natural flavoring materials available, but perhaps even moreimportantly, because of the need for materials which can combine severalnuances, will be more stable than natural materials, will blend betterwith other flavors or flavoring composition components, and willgenerally provide superior products.

There have recently been suggestions that certain pyrazine derivativeshave flavors which might be useful in foods and other consumablematerials. For example, tetramethylpyrazine has been used with vanillinin chocolate flavors, acetylpyrazine has been used in tobacco and foods,and methoxypyrazine has been said to impart a nut-like flavor to foods.

THE INVENTION It has now been found that heretofore unknown oxycyclicpyrazines are capable of imparting a wide variety of flavors to variousconsumable materials. Briefly, the invention contemplates altering theflavors of such consumable materials by adding thereto a small butefiective amount of at least one oxycyclic pyrazine having the formula3,764,349 Patented Oct. 9, 1973 wherein Y represents --CH or CH -CH Z isa carbonyl oxygen, a hydroxyl group, or an acyloxy group; and R R R andR represent hydrogen, alkyl, or alkylene and are the same or diiferent.The invention also contemplates flavoring and flavor-enhancingcompositions containing such pyrazines, as well as the novel pyrazinesand the processes for preparing them.

More specifically, the oxycyclic pyrazines according to this inventionare pyrazines to the b side of which are fused fiveand six-memberedoxygen substituted rings, such as cyclopenta and cyclohexa rings. Suchrings are substituted with a hydroxy, acyloxy, or carbonyl oxygen atomand can be substituted with one or two alkyl or alkylene groups, and thepyrazine ring can also be substituted with one or two alkyl or alkylenegroups. In some instances one or the other of the rings can besubstituted with an alkadienyl group.

The oxygen substituent can be a carbonyl oxygen so that the novelmaterial is a cyclic ketone or it can be hydroxy or acyloxy. The loweracyloxy groups containing from two to four carbon atoms are desirablyused herein. The substituents R R R and R, are preferably hydrogen orlower alkyl containing from one to six carbon atoms.

Exemplary of the oxycyclic pyrazines contemplated herein areS-acetoxy-S,6,7,8-tetrahydroquinoxaline having the structure N K N/ Thisis a white solid melting at 64.866.0 C. having a light, nut-like odor.

5oxo-5,6,7,8 tetrahydroquinoxaline having the structure is alsocontemplated. This is a yellow solid having a roasted cereal aroma, anda melting point of 57.4"- 598C.

The novel pyrazines prepared according to the present invention can beobtained by a number of reaction routes. The acyloxy derivatives mu beprepared by reacting a cyclohexapyrazine or a cyclopentapyrazine with aperacid in the presence of the corresponding lower alkanoic acid andtreating the reaction product with an aliphatic carboxylic acidanhydride. The peracid can be a lower aliphatic peracid such asperacetic, perpropionic and like acids.

The aforesaid cycloalkylpyrazine can be prepared by a number of reactionroutes, as for example by reacting a Z-halocycloalkane, e.g.,Z-chlorocyclohexanone, or an alkyl-substituted 2-halocycloalkanone, withethylene diamine or a l-alkyl or a 1,2-dialkyl derivative thereof toobtain the dihydropyrazine and then dehydrogenating the pyrazine ring,as for example by passing oxygen through a solution of the pyrazine.With 2-chlorocyclohexanone and ethylene diamine, 5,6,7,8tetrahydroquinoxaline is produced.

The quantity of peracid used is desirably at least stoichiometric withthe quantity of pyrazine derivative used so as to obtain high reactioncompletion. Excesses of peracid up to 20 percent can be used, butquantities in excess of this are wasteful of the reactants, complicaterecovery of the product, and can produce unwanted side reactions. It isaccordingly desirable to utilize peracid in quantities of fromstoichiometric to a 20 percent excess.

The reaction is carried out at temperatures above 60 C. to providedesirable reaction velocities. On the other hand, temperatures above 120C. can cause an overly vigorous reaction with the production of unwantedhighly oxidized and other undesirable by-products. It is accordinglydesirable to carry out the reaction at from 60 to 120 C. It has beenfound that good results can be obtained in the preferred temperaturerange of from 70 to 85 C.

This step of the reaction takes place readily. Generally, the minimumlength of time is governed by the rate at which the peracid can be addedwithout creating an excessive temperature rise, and in the usual processequipment this can be as little as about 15 minutes. On the other hand,an additional holding period after peracid addition has been completedwill serve to provide high completeness, and an additional hour or twois generally suificient for this purpose. Accordingly, this phase of theprocess is carried out for from about 15 minutes to about two hours.

An alkanoic acid is used as a reaction vehicle and moderator to providebetter control over the process. Generally, the use of lower alkanoicacids is desirable, and acids having from two to four carbon atoms arepreferred.

The alkanoic acid is preferably stripped off and the product of peracidtreatment is then treated with an alkanoic acid anhydride. The anhydrideused is preferably a lower alkanoic acid anhydride, that is an anhydrideof an aliphatic acid having from two to four carbon atoms.

The anhydride treatment is carried out at temperatures of from 80 to 140C. It is preferred to carry out the reaction at the reflux temperatureof the anhydride.

The quantity of anhydride utilized should be at least stoichiometricwith the cyclic pyrazine used, and it is desirable that excesses of from100 to 200 percent of the anhydride be used. The treatment withanhydride is carried out for from about one to about six hours, andtimes of from one to two hours are preferred.

The corresponding hydroxy derivative is readily produced from theacyloxy derivative by hydrolysis with aqueous or alcoholic alkali metalhydroxide. The hydrolysis is carried out at temperatures of from about60 to about 100 C. to provide good reaction rates and completeness infrom one to four hours. The hydroxides of sodium and potassium aredesirably used, and methanol is a preferred alcohol.

The corresponding ketone is conveniently produced by oxidation of thealcohol. The oxidation can be carried out in a solvent or vehicle suchas dimethyl sulfoxide with a lower alkanoic anhydride such as those setforth above.

The reaction is carried out at mild temperatures of from 15 to 30 C.,and preferably at 2025 C. Times of from eight to 48 hours are used,depending upon the temperature, the reactants, the vehicle, amount ofagitation and the like. Jones reagent (one mole of chromium trioxide, A;mole of sulfuric acid, and acetone in an amount about five times theweight of the trioxide) can also be used as an oxidizing agent in thisstep.

It will accordingly be apparent to those skilled in the art that apreferred route begins with the peracid oxidation of a compound havingthe formula wherein R is alkyl, preferably having one to three carbonatoms.

It will be understood by those skilled in the art that the intermediateand the final products prepared herein can be neutralized, washed, anddried to purify and cleanse the desired substances. The novel oxycyclicpyrazines can be obtained in purer form or in substantially pure form byconventional purification techniques. Thus, the products can be purifiedand/or isolated by distillation, extraction, preparative chromatographictechniques, and the like. It has been found desirable to purify theoxycyclic pyrazines by fractional distillation under vacuum.

It will be appreciated from the present disclosure that the oxycyclicpyrazines and mixtures thereof according to the present invention can beused to alter, vary, fortify, modify, enhance, or otherwise improve theflavor of a wide variety of materials which are ingested, consumed, orotherwise organoleptically sensed. Such pyrazines are accordingly usefulin flavoring compositions and in flavorenhancing compositions. Aflavor-enhancing composition is taken to mean one which contributes apart of the overall flavor impression by supplementing or fprtifying anatural or artificial flavor in a material.

When the pyrazines of this invention are used in a flavoring or aflavor-enhancing composition, they can be combined with conventionalflavoring materials including organic acids such as fatty, saturated,unsaturated, and amino acids; alcohols, including primary and secondaryalcohols; esters; carbonyl compounds including ketones and aldehydes;lactones; other cyclic organic materials including benzene derivatives,alicyclics, heterocyclics such as furans, pyridines, other pyrazines andthe like; sulfur-containing materials including thiols, sulfides,disulfides and the like; proteins; lipids, carbohydrates; socalledflavor potentiators such as mono-sodium glutamate, guanylates, andinosinates; natural flavoring materials such as cocoa, vanilla, andcaramel; artificial fiavoring materials such as vanillin; and the like.

It will be appreciated that the types and amounts of materials selectedfrom the foregoing groups of materials will depend upon the preciseorganoleptic character desired in the finished product and, especiallyin the case of flavoring compositions used to enhance other flavors,will vary according to the foodstuff to which flavor and aroma are to beimparted. Inorganic materials such as sodium chloride and freshnesspreservers such as butylated hydroxyanisole and propyl gallate can beadded for their adjuvant or preservative effects on the flavoringcomposition.

The pyrazines, or the compositions incorporating them as mentionedabove, can be combined with one or more vehicles or carriers for addingthem to the particular product. Vehicles can be edible or otherwisesuitable materials such as ethyl alcohol, propylene glycol, water, andthe like. Carriers include materials such as gum arabic, carrageenen,other gums, and the like. The pyrazines can be incorporated with thecarriers by conventional means such as spray-drying, and the like. Suchcarriers can also include materials for coacervating the pyrazines (andother flavoring ingredients( as present) to provide encapsulatedproducts. When the carrier is an emulsion, the flavoring composition canalso contain emulsifiers such as monoand diglycerides of fatty acids andthe like. With these carriers or vehicles the desired physical form ofthe composition can be prepared.

It will be understood by those skilled in the art that the pyrazinesaccording to this invention can be added to the materials to be flavoredat any convenient point in the production of the finished product. Thus,when the pyrazines are used to alter or otherwise vary the flavor of afoodstuff, they can be added in the original mixture, dough, emulsion,batter, or the like prior to any cooking or heating operation.Alternatively, they can be added at a later stage of processing ifvolatilization losses would be excessive during the earlier processing.

When the materials are used to treat tobacco products, for example, theadditives can be applied in a suitable manner by spraying, dipping, orotherwise. The pyrazines can be appled to the casing or final spraytreatment of the tobacco, or they can be applied at some earlier stageof curing. The quantity of pyrazines or mixtures thereof utilized shouldbe suflicient to impart the desired flavor characteristic to theproduct, but on the other hand, the use of an excessive amount of thepyrazines is not only wasteful and uneconomical but in some instancestoo large a quantity may unbalance the flavor or other organolepticproperty of the product to be consumed. The quantity used will varydepending upon the ultimate foodstuff, tobacco product, or otherconsumable product; the quantity of flavor present initially in theproduct; the further process or treatment steps to which the productwill be subjected; regional and other preference factors;'

the type of storage, if any, to which the product will be subjected; andthe pre-consumption treatment, such as baking, frying, and so on, givento the product by the ultimate consumer.

It is accordingly preferred that the ultimate compositions contain fromabout 0.1 p.p.m. to about 100 p.p.m. More particularly, in foodcompositions it is desirable to use from about to about 50 p.p.m. and incertan preferred embodiments of the invention, from about to about 50p.p.m. of the pyrazines are included in the finished product. On theother hand, tobacco compositions can contain as little as 0.1 p.p.m. andas much as 100 p p.m., depending upon whether a cigarette tobacco, apipe tobacco, a cigar tobacco, a chewing tobacco, or snufl is beingprepared.

The amount of pyrazine or pyrazines to be utilized in flavoring orflavor-enhancing composition can be varied over a wde range dependingupon a particular quality to be added to the foodstuff, tobacco, orother consumable material. Thus, amounts of one or more pyrazinesaccording to the present invention from about 0.1 up to 80 or 90% can beincorporated in such compositions. It is generally found to be desirableto include from about 0.5 to about 25% of the oxycyclic pyrazines insuch compositions.

The following examples are given to illustrate embodiments of theinvention as it is presently preferred to practice it. It will beunderstood that these examples are illustrative, and the invention isnot to be considered as restricted thereto except as indicated in theappended claims.

EXAMPLE I Preparation of 5-acetoxy-5,6,7,8- tetrahydroquinoxaline Aone-liter reaction flask fitted with an agitator, thermometer, refluxcondenser and addition funnel is charged with 200 cc. of acetic acid,and 53.6 g. (0.4 mole) of 5,6,7,S-tetrahydroquinoxaline is added. Themixture is brought to 75 C. and 76.0 g. (0.4 mole) of 40% peracetic acidis added dropwise during 20 minutes, while the flask temperature ismaintained at 75il C. with cooling. The yellow solution is then stirredat 75 C. for 45 minutes.

The flask contents are subjected to reduced pressure to remove theacetic acid, and the residue is refluxed with 400 ml. of aceticanhydride for 1 /2 hours. While the mixture is being heated up, itassumes a dark brown color. The acetic anhydride remaining is thenremoved under reduced pressure.

The flask contents are cooled to room temperature, and 500 ml. of ethylether is added. After adding one liter of water, the organic layer isdecanted, and the aqueous layer is extracted thrice with 300 ml.portions of ethyl ether. The ether extracts are combined with theorganic layer and washed successively with equal volumes of saturatedaqueous sodium chloride solution, saturated aqueous sodium bicarbonate,and saturated aqueous sodium chloride solution. The washed material isdried over magnesium sulfate, and the ether is removed by evaporation toobtain 70.0 g. of crude product.

The material is re-extracted with 350 ml. of chloroform, the extract isdried over magnesium sulfate, and the chloroform is evaporated to obtain1.5 g. of organic material, of which about one gram is the acetoxyderivative.

The organic material is distilled in a Vigreaux column at 1 28-140 C.and 2.8-14 mm. Hg to obtain 1.0 g. ofS-acetoxy-S,6,7,S-tetrahydroquinoxaline.

The pale yellow liquid boils at 128l29 C. at 0.7 mm. Hg and has an 11 of1.5293. At the 200 p.p.m. level in beef broth it accentuates the brothyaroma. A 2 p.p.m. aqueous solution has a light popcorn flavor note, anda 10 p.p.m. aqueous solution has a popcorn flavor note with a lightbitter aftertaste. In peanut butter, this material provides a lightroast peanut flavor.

EXAMPLE II Preparation of 5-hydroxy-5,6,7,8-tetrahydroquinoxaline A 500ml. flask fitted with a mechanical agitator and reflux condenser ischarged with 1.5 g. of 5-acetoxy-5,6, 7,8-tetrahydroquinoxaline and asolution of 12 ml. of 20% aqueous potassium hydroxide in 30 ml. ofmethanol. The flask contents are then refluxed for 1 /2 hours, andthereafter the methanol is stripped away under vacuum. Then 60 ml. ofwater is added, and the resulting liquid is extracted thrice with ethylether.

The ether extract is dried over magnesium sulfate, and the other isstripped off. The 0.7 g. residue is dissolved in 4 ml. of petroleumether containing a few drops of ethyl ether and held at 0 to 5 C.overnight. The liquid is decanted from the resulting precipitate.

The product is obtained after purification by vacuum distillation as awhite solid melting at 64.8-66.0 C. Proton magnetic resonance (PMR)shows an absorption at 8.41 p.p.m. attributable to two aromatic protons;an absorption at 4.80 p.p.m. attributable to a proton substituent on ahydroxylated carbon atom adjacent to a pyrazine ring; an absorption at4.08 p.p.m. attributable to a hydroxyl proton; an absorption at 3.00p.p.m. attributable to protons in a methylene group adjacent to apyrazine ring; and absorption at 2.40-1.70 p.p.m. attributable to thefour protons in two methylene groups one carbon atom removed from apyrazine ring. The odor of a 2 percent alcoholic solution has a fatty,nut-like note, and a 6 p.p.m. aqueous solution has a sweet flavor note.

Mass spectroscopy of the material shows a parent peak at 150 and otherpeaks at 94, 122, 121, and 39.

EXAMPLE III Preparation of S-oxo-5,6,7,8-tetrahydroquinoxaline A mixtureis prepared by combining 0.50 g. (3 millimoles) ofS-hydroxy-S,6,7,S-tetrahydroquinoxaline, 9 ml. of dimethyl sulfoxide,and 6 ml. of acetic anhydride, and the mixture is then permitted tostand at room temperature (23 C.) for 24 hours. At the end of thisperiod the mixture is poured into 50 ml. of water and the aqueous layeris extracted thrice with 20 ml. portions of methylene chloride. Themethylene chloride extracts are combined and acidified with 25 ml. of20% sulfuric acid.

The aqueous layer is separated and washed once with an equal volume ofether. The aqueous layer is then made alkaline with a 20% aqueouspotassium hydroxide solution and extracted three times with 15 ml.volumes of methylene chloride. The methylene chloride extract is driedover magnesium sulfate, and the solvent is evaporated.

The evaporation leaves 0.40 g. of -oxo-5,-6,7,8-tetrahydroquinoxaline.This material is a yellow crystalline solid melting at 57.4-59.8 C. PMRshows absorption at 8.64 p.p.m. attributable to two aromatic protons; atriplet at 3.24 p.p.m. attributable to two protons on a methylene groupinterposed between a methylene group and a carbonyl group adjacent apyrazine ring; a triplet at 2.84 p.p.m. attributable to two protons in amethylene group adjacent a pyrazine ring; and a quintet at 2.24 p.p.m.attributable to two protons on a methylene group intermediate amethylene group adjacent to a pyrazine ring and a methylene groupadjacent to a carbonyl group substituent on a pyrazine ring. Massspectral analysis of the oxomaterial shows a parent peak at 148 andother peaks at 119, 92,120, 41, 39 and 65.

Addition of this material to chicken broth at the 3 p.p.m. level deepensthe parsley character. It can be used in spice flavors where light,spicy, earthy flavor notes are desired, e.g., paprika, nutmeg.

EXAMPLE IV A cheddar cheese flavoring formulation is prepared byadmixing the following ingredients in the amounts indicated:

Produced in Example I The foregoing cheese formula is incorporated intoa bland cream cheese dip and evaluated. A good strong cheese note isimparted to the dip.

Similarly, other flavors can be improved by adding the acetoxyderivative prepared in Example I or the hydroxy and/or oxo derivativesof Example H and Example [11.

What is claimed is:

1. A process for altering the flavor or aroma of a consumable materialwhich comprises adding thereto a small but effective amount of at leastone oxycyclic pyrazine of the formula wherein Y is -CH or CH CH Z is =0,an hydroxy group, or an alkanoyl group having from two to four carbonatoms; and R R R and R are the same or different and represent hydrogenor lower alkyl having one to three carbon atoms.

2. A process as defined in claim 1 wherein Y is -CH CH Z is =0 and R R Rand R are hydrogen.

3. A process as defined in claim 1 wherein Y is OH CH Z is hydroxy; andR R R and R are hydrogen.

4. A process as defined in claim 1 wherein Y is CH CH Z is acetyloxy andR R R and R are hydrogen.

5. A flavoring composition comprising at least one oxycyclic pyrazine ofthe formula References Cited FOREIGN PATENTS 3/1969 Netherlands.

OTHER REFERENCES Sax: Dangerous Properties of Industrial Materials, 3rded. Reinhold Book Corp., N.Y. (1969), p. 934.

Condensed Chemical Dictionary, 8th ed., Van Nostrand Reinhold Co., NY.(1971), pp. 619 and 622. Henderson et al.: Noxious Gasses, ChemicalCatalog Co., Inc., New York (1927), pp. 134-136.

MORRIS O. WOLK, Primary Examiner S. MARANTZ, Assistant Examiner US. Cl.X.R.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent NQ.3,764,349 Dated October 9 1973 Inventor s BRAJA D. MOOKHERJEE et a1 Itis certified that error appears in the above-identified patent and thatsaid Letters Patent are hereby corrected as shown below:

Page 2, line 7, after "or" correct the formula to read: CH CH Signed andsealed this 23rd day of April 19714..

(SEAL) Attest:

EDWARD I-T.FLETGHER,JR. C. MARSHALL DANN Attesting Officer Commissionerof Patents

